Mechanisms of oral immunotherapy-induced suppression of type I hypersensitivity.

描述(由申请人提供)：食物过敏研究联盟(COFAR)已经开始了一系列研究，旨在解决食物过敏的病因和潜在的治疗方法。其中一项计划中的临床试验将评估逐步口服花生过敏原(口服免疫疗法或OIT)在保护患者免受过敏反应并最终治愈他们过敏方面的有效性。花生过敏患者对花生过敏原有免疫反应，导致免疫球蛋白E(IgE)的产生。免疫球蛋白被免疫细胞上的受体结合，如嗜碱性细胞，当它与花生过敏原接触时，会导致组胺和其他物质的释放。研究表明，OIT能诱导过敏原特异性免疫球蛋白G(Ig G)抗体的产生。这种免疫球蛋白抗体与免疫球蛋白E抗体相比，可能具有保护作用，但其保护机制尚不清楚。此外，通过一种鲜为人知的被称为“临床脱敏”的过程，它似乎通过使人们对额外的意外暴露不那么敏感来保护人们免受严重反应的影响。以前的研究表明，免疫球蛋白通过与嗜碱性粒细胞上抑制的免疫球蛋白受体相互作用来抑制IgE，尽管其他研究表明，免疫球蛋白可能只是简单地阻止变应原与IgE结合。到目前为止，还没有研究设计成允许在临床试验的背景下对这些替代机制进行个体评估。我们假设，OIT诱导抑制性免疫变化，从而阻止IgE诱导的嗜碱性粒细胞释放组胺。我们想通过三个目标来检验我们的假设：首先，我们想要确定OIT诱导抑制性免疫球蛋白的频率。其次，我们想要确定的是，免疫球蛋白主要是阻断IgE的过敏原，还是与嗜碱性粒细胞上的抑制性受体相互作用。第三，我们想了解过敏原的逐渐引入和快速(几小时到几天)升级到以前会引起反应(临床脱敏)的剂量是如何影响患者的嗜碱性细胞的。为了做到这一点，我们打算利用我们在用流式细胞仪测量嗜碱性细胞激活方面的积累经验，首次开始直接检测通过IgE和Ig G受体刺激细胞所产生的细胞内信号。我们相信，我们有一个独特的机会来进行一项小型的、自给自足的研究项目，以补充已经资助的一项针对食物过敏的口服免疫疗法的大型前瞻性临床研究。该项目有可能为口服免疫治疗的机制提供新的和独特的见解，并通过直接测量细胞内信号分子来建立评估嗜碱性细胞激活的创新方法。 公共卫生相关性食物过敏影响6-8%的儿童和2-4%的成年人，而且还在增加。食物过敏导致大约30,000例过敏反应和100-200例死亡。这项建议是为了研究过敏原免疫疗法如何保护人们，从而最终使其更加有效。

DESCRIPTION (provided by applicant):The Consortium of Food Allergy Research (CoFAR) has begun a series of studies intended to address both the etiology of and potential cure for food allergy. One of the planned clinical trials will evaluate the effectiveness of gradually administering peanut allergen by mouth (oral immunotherapy or OIT) on protecting patients from allergic reactions and ultimately curing them of their allergy. Patients with peanut allergy have an immune response to peanut allergens that results in the production of immunoglobulin E (IgE). IgE is bound by receptors on immune cells, such as basophils, and can lead to the release of histamine and other substances when it comes into contact with peanut allergen. It has been shown that OIT can induce the production of allergen-specific immunoglobulin G (IgG) antibody. This IgG antibody, in contrast to IgE antibody, may be protective, though the mechanism of its protection is not well understood. In addition, by a poorly understood process termed, `clinical desensitization', OIT appears to protect people from severe reactions by making them less sensitive to additional accidental exposures. Previous studies have suggested that IgG inhibits IgE by interacting with inhibitory IgG receptors on basophils, although other studies have suggested instead that IgG may simply prevent allergen from binding to the IgE. To date, no studies have been designed in such a way as to allow evaluation of these alternative mechanisms on an individual basis in the context of a clinical trial. We hypothesize, that OIT induces inhibitory immune changes that prevent the IgE-induced release of histamine from basophils. We would like to test our hypothesis by focusing on three aims: First, we would like to establish how frequently inhibitory IgG is induced by OIT. Second, we would like to determine whether IgG is primarily blocking allergen from IgE or interacting with inhibitory receptors on basophils. Third, we would like to understand how gradual introduction and rapid (hours to days) escalation of allergen to a dose that would previously have caused a reaction (clinical desensitization) affects patients' basophils. In order to do this, we intend to take advantage of our cumulative experience in measuring basophil activation by flow cytometry, and begin for the first time to directly examine intracellular signals that result from the stimulation of the cells via the IgE and IgG receptors. We believe we have a unique opportunity to conduct a small, self-contained research project that complements an already funded large prospective clinical study of oral immunotherapy for food allergy. This project has the potential both to give new and unique insight into the mechanisms of oral immunotherapy and to establish innovative methods for the assessment of basophil activation by direct measurement of intracellular signaling molecules. PUBLIC HEALTH RELEVANCE Food allergy affects 6-8% of children and 2-4% of adults and is increasing. Food allergy accounts for approximately 30,000 episodes of anaphylaxis and 100-200 deaths. This proposal is to study how allergen immunotherapy can protect people so that ultimately it can be more effective.